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J Mol Cell Cardiol. 2015 Dec;89(Pt B):365-75. doi: 10.1016/j.yjmcc.2015.09.018. Epub 2015 Oct 1.

Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium.

Author information

1
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
2
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Department of Pharmacology, School of Medicine, University of California Davis, Genome Building, 451 Health Sciences Drive, Davis, CA 95616, USA.
3
Department of Cardiology, Charité-Universitaetsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
4
Division of Endocrinology and Metabolism, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Division of Cardiac Surgery, Department of Surgery, Medical University of Graz, Auenbruggerplatz 29, 8036 Graz, Austria.
5
Safety Pharmacology, Worldwide Research and Development, Pfizer Inc., Groton, CT 06340, United States.
6
Cardiovascular and Metabolic Diseases Research Unit, Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139, United States.
7
Worldwide Medicinal Chemistry, Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139, United States.
8
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria; Department of Cardiology, Charité-Universitaetsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.
9
Department of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Electronic address: dirk.von-lewinski@medunigraz.at.

Abstract

Glucagon-like peptide-1 receptor (GLP-1R) agonists are a rapidly growing class of drugs developed for treating type-2 diabetes mellitus. Patients with diabetes carry an up to 5-fold greater mortality risk compared to non-diabetic patients, mainly as a result of cardiovascular diseases. Although beneficial cardiovascular effects have been reported, exact mechanisms of GLP-1R-agonist action in the heart, especially in human myocardium, are poorly understood. The effects of GLP-1R-agonists (exenatide, GLP-1(7-36)NH2, PF-06446009, PF-06446667) on cardiac contractility were tested in non-failing atrial and ventricular trabeculae from 72 patients. The GLP-1(7-36)NH2 metabolite, GLP-1(9-36)NH2, was also examined. In electrically stimulated trabeculae, the effects of compounds on isometric force were measured in the absence and presence of pharmacological inhibitors of signal transduction pathways. The role of β-arrestin signaling was examined using a β-arrestin partial agonist, PF-06446667. Expression levels were tested by immunoblots. Translocation of GLP-1R downstream molecular targets, Epac2, GLUT-1 and GLUT-4, were assessed by fluorescence microscopy. All tested GLP-1R-agonists significantly increased developed force in human atrial trabeculae, whereas GLP-1(9-36)NH2 had no effect. Exendin(9-39)NH2, a GLP-1R-antagonist, and H-89 blunted the inotropic effect of exenatide. In addition, exenatide increased PKA-dependent phosphorylation of phospholamban (PLB), GLUT-1 and Epac2 translocation, but not GLUT-4 translocation. Exenatide failed to enhance contractility in ventricular myocardium. Quantitative real-time PCR (qRT-PCR) revealed a significant higher GLP-1R expression in the atrium compared to ventricle. Exenatide increased contractility in a dose-dependent manner via GLP-1R/cAMP/PKA pathway and induced GLUT-1 and Epac2 translocation in human atrial myocardium, but had no effect in ventricular myocardium. Therapeutic use of GLP-1R-agonists may therefore impart beneficial effects on myocardial function and remodelling.

KEYWORDS:

Diabetes mellitus; GLP-1; Inotropic agents; Myocardial contraction; Signal transduction

PMID:
26432951
DOI:
10.1016/j.yjmcc.2015.09.018
[Indexed for MEDLINE]

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